The human immunodeficiency virus (HIV) envelope glycoprotein and tetanus toxoid (TT) represent the two extremes of immunogenicity. Vaccination with HIV envelope protein usually induces a weak and transient immune response. In striking contrast, vaccination with tetanus toxoid induces potent T and B cell responses that persist for decades. In many instances, people vaccinated with tetanus toxoid have circulating antibody in the serum for over 25 years. The answer to the question as to why is tetanus so effective in inducing long-term immunity and the HIV glycoprotein so inefficient, is not known, but there are several possible reasons for the striking differences in the immunogenicity of these proteins, including: (i) tetanus may have strong T and B cell epitopes that are lacking in HIV envelope protein; (ii) tetanus may have a special propensity to persist in vivo in the form of antigen-antibody complexes on follicular dendritic cells (FDC). This antigen depot FDC would be critical in sustaining antibody responses by providing a stimulus for the continuous differentiation of memory B cells into antibody secreting plasma cells, and (iii) the heavy glycosylation of HIV envelope protein may mask potential T and B cell epitopes. The goal of this proposal is to enhance the immunogenicity of HIV envelope by making fusion proteins with tetanus and also by altering potential glycosylation sites. This approach is not without risk, but it has the potential for providing a better AIDS vaccine, and almost certainly will yield preliminary data that will be useful in understanding the immunological properties of HIV envelope glycoprotein - a key protein for targeting anti-HIV immune responses. Also, the proposed studies may reveal whether, in principle, it is possible to enhance immunogenicity of HIV glycoprotein by incorporation of T and B cell epitopes from a highly immunogenic protein, such as tetanus toxoid. The specific aims of the proposed studies are as follows: (1) to construct chimeric proteins between tetanus and HIV gp120 (and SIV gp120); and (2) to test the immunogenicity of several chimeric proteins and to try out various prime/boost protocols. The initial experiments will be done in mice and then selected chimeric proteins will be tested in rhesus macaques for immunogenicity and protective immunity (SIV and SHIV challenge experiments).